A lamb model of persistent pulmonary hypertension of the newborn (PPHN) has been created by inducing chronic intrauterine hypoxia secondary to embolization of the maternal side of the placenta with nonradioactive microspheres beginning at 115 days gestation (term equals 147 days). In utero studies have shown significant elevation of fetal renin and arginine vasopressin in association with hypoxia and/or acidosis. In the adult, and probably in the fetus, renin forms the highly vasoactive substance angiotensin II which has been considered by several researchers to be implicated in the pathogenesis of hypoxic pulmonary hypertension. Arginine vasopressin may create systemic hypertension thereby exposing the fetal pulmonary circulation to a stimulus which has been shown to increase pulmonary arteriolar medial smooth muscle. A highly successful experimental technique of quantitating pulmonary vascular reactivity in intact newborn lambs has been developed also. Using this preparation and the chronically embolized lamb model, we will study the factors which control activation of the renine angiotensin system and its maturation through the final trimester of sheep pregnancy. The influence of angiotensin II directly on the pulmonary vascular bed will be studied by microsphere technique in the fetus, and direct measurement of pulmonary pressure and blood flow in the neonate. The influence of the renin angiotensin system in the development of PPHN will be studied with blocking agents in both preparations. The role of arginine vasopressin in fetal circulatory control will be similarly studied. Because PPHN may be cause by abnormal increase in pulmonary vascular smooth muscle, experimental and control lambs will have quantitative pathologic studies performed. Finally, potentially clinically useful pulmonary vasodilating drugs (tolazoline, prostaglandin E1, and acetylcholine) will be evaluated in both the normal and chronically hypoxic newborn lamb preparation.